Project Summary/Abstract There is a significant unmet clinical need to find effective analgesic drugs for the treatment of chronic pain that have fewer adverse effects, tolerance development, and abuse potential. We have identified a novel mixed efficacy opioid ligand (AAH8) that is highly effective for treating pain in animal models but does not produce tolerance or dependence when administered repeatedly. This compound appears to have minimal rewarding effects in an animal model. These data suggest that our candidate compound may be the ultimate opioid analgesic that produces significant pain relief with little risk of developing tolerance or addiction. AAH8 has equivalent affinity for mu and delta opioid receptors but it is a mu opioid receptor agonist and a delta opioid receptor antagonist and appears to cross the blood brain barrier. Blocking delta-opioid receptors has been proposed to alter the trafficking of mu-opioid receptors as related to desensitization, downregulation, and tolerance. While it is unusual to think that an effective mu-opioid analgesic would not have abuse potential, our preliminary data suggest that the mixed efficacy opioid ligand marks a significant improvement over current opioid analgesics, especially for treating chronic pain. Therefore, the long-term goal of the proposed work is to identify effective treatments for chronic pain with fewer adverse consequences associated with long term treatments. The objective here is to examine the effects of AAH8 in models of chronic pain, drug self- administration, and adverse side effects as compared with clinically used opioid analgesics. The overarching hypothesis is that AAH8 will have limited reinforcing effects in a drug self-administration assays and will retain efficacy in chronic pain assays. To accomplish this work, AAH8 will be evaluated in a chronic pain models and in drug self-administration assays in opioid-nave and -experienced subjects to determine its reinforcing effects. Overall, this venture has the potential to identify a drug that would dramatically improve the treatment and management of chronic pain by reducing the hazards associated with long term opioid treatment.